Among the variety of compounds that have consistently been found to possess potent and selective biological activity are natural products and peptides. Indeed, members of these classes have become useful pharmaceutical agents. Unfortunately, each type has limitations that have restricted the wider utility of these structures.
In fact, natural products often have extremely complex structures that are difficult to synthesize, particularly in the combinatorial fashion that would provide access to a greater number of analogues with which to define pharmacophoric elements and best explore modulation of the biological properties of the parent compound. Nevertheless, some efforts have been successful at constructing natural product libraries containing a modest number of analogues.
Peptides, on the other hand, have been at the forefront of the development of combinatorial chemistry due to their ease of synthesis on solid support, the reproducible and high-yielding reactions involved, and the ready availability of starting materials. Peptides being the endogenous ligands for a number of enzymes and receptors, their modification can be performed to develop even more potent agonists or inhibitors of these same receptors and enzymes. In addition, combinatorial peptide libraries have been used to find a number of previously unknown active sequences for a wide array of enzyme and receptor systems.
However, peptidic compounds are plagued by the usual limitations associated with the direct use of peptides as pharmaceuticals, including rapid metabolic degradation by proteases, short pharmacokinetic half-life, difficulty in transport to site of action in tissues and organs, poor oral bioavailability and solubility, potential antigenicity, as well as high manufacturing costs.
Nevertheless, the densely functionalized and structurally diverse nature of peptides is advantageous when seeking new drug molecules. Hence, peptides are primarily used as the starting point or template for the development of new pharmaceutical leads that often results in structures that only partially resemble, if at all, the initial active peptide. In particular, the recognition potential of the amino acid side chains has resulted in attempts to incorporate these side chains into non-peptidic rigid scaffolds that attempt to duplicate the conformational display required for optimal interaction between the molecule and the target, as well as mimic standard protein and peptide secondary structural elements. For example, sugars and aromatic rings have been exploited as rigid scaffolds containing amino acids or analogues as pendant moieties at one or more positions. Compounds and combinatorial libraries utilizing 3- and 4-substituted pyrrolidines as a central template for display of interacting functionality have been disclosed in U.S. Pat. Nos. 5,646,285 and 5,891,737.
In another approach, cyclic structures can greatly improve the pharmacological and pharmacokinetic profiles of peptides (Molecular Diversity 2000 (pub. 2002), 5, 289-304). Cyclic peptides analogues offer a number of benefits compared with the corresponding linear analogues, including restricted conformational mobility, defined topology, enhanced stability to proteolytic enzymes and modified polarity. Furthermore, cyclic peptides can enhance potency, selectivity, stability, bioavailability and membrane permeability. The stability to enzymatic degradation of the cyclic structure arises from the difficulty of such molecules to attain the extended conformation required to be recognized as a substrate for peptidases. Very large mixture libraries (108 members or more) of cyclic peptides have been described in WO 98/54577.
However, larger rings are often too flexible and can occupy too many conformations to be useful. Further, their molecular size and resulting physicochemical characteristics do not fit the typical requirements for being “drug-like.” Small cyclic peptides containing the key interacting residues would provide the necessary conformational restriction, but may have other disadvantages, including synthetic difficulty, ease of dimerization, unfavorable ring strain caused by the presence of the preferred trans amide bonds, lack of stability towards metabolism and hydrolysis to release that strain and limited topological diversity.
Most attention in combinatorial chemistry has been devoted to producing diversity in terms of chemical composition. However, essentially no effort has been directed at integrating this with diversity in terms of the crucial three-dimensional structure.
The use of certain tether elements to control conformation was reported in WO 01/25257. However, although those tethers were successful in restricting the conformational display of the molecule, they only were able to duplicate a portion of the spatial region accessible to a linear molecule, which can contain hundreds if not thousands of possible conformations. To better cover the available conformational space, additional tether elements that define new conformations are required. In addition, the tethers in the previous report were generally hydrophobic in nature. This effects key properties of the macrocyclic molecules such as solubility and log P that are known to have an impact on the compound's pharmacological properties, in particular oral bioavailability. Further, variation of these physicochemical properties is often required in order to optimize the desired characteristic of a molecule as a therapeutic agent. As well, the early tethers were rather limited in their chemical functionality. Since this part of the molecule also could have interactions with a biological target in addition to its conformational control function, a greater diversity in the chemical functional groups could prove advantageous. The more chemically diverse tethers of the present invention therefore have been designed to address these limitations of the existing art and provide the following benefits:                Access to previously inaccessible conformations        Modification of physicochemical parameters        Improvement of pharmacokinetic profile        Additional interacting functionalities for modulation of biological activity        
Growing evidence suggests that molecular rigidity confers favorable pharmacokinetic properties on molecules and leads to improved clinical success (J. Med. Chem. 2003, 46, 1250-1256; J. Med. Chem. 2002, 45, 2615-2623). The tethers of the present invention therefore will be extremely useful in utilizing these macrocyclic molecules in the search for new pharmaceuticals. Examples of the activity that have been exhibited by representative molecules of the invention are provided.
Therefore, there remains a need for specifically designed chemical entities built on a macrocyclic framework, which exploit the three-dimensional conformation changes triggered by peptidic modifications and/or by inserting specific tether-like portions, in their macrocyclic skeleton.